This invention relates to a method for the preparation of 2,4,5-trifluorobenzoic acid by the decarboxylation of 3,4,6-trifluorophthalic acid. 2,4,5-trifluorobenzoic acid is a useful intermediate in the manufacture of quinolone antibacterial drugs.
Heretofore, 2,4,5-trifluorobenzoic acid has been difficult to synthesize. One known method of synthesis involves the cyanation of 2,4,5-trifluorobromobenzene using copper cyanide in dimethyl formamide, followed by hydrolysis of the product nitrile with sulfuric acid [Sanchez, J. P. et al J. Med. Chem. (1988), 31, 983]. This synthetic method is difficult to use, and expensive.
We have now discovered that 2,4,5-trifluorobenzoic acid may be prepared by the decarboxylation of 3,4,6-trifluorophthalic acid. The reaction may be conducted in dipolar aprotic solvents, without the use of a catalyst. Surprisingly, only one of the two carboxyl groups is removed, and 2,4,5-trifluorobenzoic acid is produced in good yield. 3,4,6-Trifluorophthalic acid may be conveniently prepared from 3,4,6-trichlorophthalic acid. The acid is reacted with aniline to form 3,4,6-N-phenylphthalimide. The phthalimide is then treated with potassium fluoride in sulfolane using tributylhexadecylphosphonium bromide as a phase transfer catalyst. The method is disclosed in copending patent application Ser. No. 07/315,746, which is hereby specifically incorporated by reference.
Many examples of decarboxylation reactions have been reported. Basic substances have been used to catalyze such reactions. For example, it is disclosed in D. S. Tarbell, et al Org. Syn., III coll. vol. (1955) 267, that 3,5-dichloro-4-hydroxybenzoic acid may be decarboxylated by vigorous heating in N,N-dimethylaniline. It is disclosed in A. Singer and S. M. McElvane, Org. Syn., coll. vol. II (1943) 214, that 3,5-dicarboxy-2,6-dimethylpyridine di-potassium salt may be completely decarboxylated by heating the salt in the presence of calcium hydroxide. Copper and copper salts have been used to catalyze decarboxylation reactions. For example, H. R. Snyder et al, Org. Syn., coll. vol. III (1955) 471 disclose the use of copper oxide catalyst for the decarboxylation of imidazole-4,5-dicarboxylic acid.
Some compounds may be decarboxylated without catalysts. For example, C. Wang, Bul. Inst. Kim. Acad. Sinica, no. 2156 (1972), as abstracted in CA79 (15):91729, discloses that tetrachloro or tetrabromophthalic acids, or their anhydrides, may be decarboxylated to the corresponding benzoic acids when refluxed in dimethyl formamide. 3-nitrophthalic acid underwent a similar reaction. Under similar conditions 1,8-naphthalene dicarboxylic acid, and its 3-nitro derivative merely formed the corresponding anhydride.
Decarboxylation is not always a predictable reaction. For example, A. S. Sultanov, J. Gen. Chem. (USSR) 16 1835 (1946) as abstracted in CA 41:6223(e) discloses that salicylic acid may be decarboxylated by autoclaving the acid in the presence of copper bronze and benzene at 170.degree. C. The acid alone decarboxylates at 205.degree. C., while in the presence of aniline decarboxylation begins at 170.degree. C. In the case of salicylic acid, aniline and copper bronze seem to be equal in catalytic ability. On the other hand, when phthalic acid is heated in aniline at 180.degree. C., decarboxylation does not occur and instead phthalic anhydride is produced. Heating phthalic anhydride with copper bronze in chloroform at 180.degree. C. gave a 22% yield of benzoic acid. Phthalic acid was found to decarboxylate to yield benzoic acid merely by heating in water at 235.degree. C.
Decarboxylations of certain fluorophthalic acids have been reported. 3,4,5,6-tetrafluorophthalic acid decarboxylates under certain conditions to yield 2,3,4,5-tetrafluorobenzoic acid. For example, Japanese Patent JP 61/85349 A2[86/85349]as abstracted in CA105:152719r discloses that the reaction may be conducted in an aqueous medium at 150.degree. to 230.degree. C. The reaction may be carried out at lower temperature (100.degree. to 250.degree. C.) in the presence of copper, zinc, cadmium, iron, cobalt, nickel, other oxides, hydroxides and/or carbonates. Japanese Patent Application 86/103,317 as abstracted in CA105 (22):193368u discloses that the above reaction may be conducted in an aqueous medium at a pH of 0.7-2.2 at a temperature of 100.degree.-200.degree. C. The pH of the medium is adjusted by acidifying with sulfuric acid and partial neutralization with calcium hydroxide. Japanese Patent 63/295529m A2[88/295529](as abstracted in Chem. Abstracts CA 111 (3): 23221X) discloses that the reaction may be conducted at 130.degree. in tri-butylamine.
Small changes in structure of molecule, or conditions can result in major changes in the product produced when fluorinated phthalic acids are decarboxylated. For example, Yacobsen, O. J. discloses in Zh. Obsch. Khim. 36 (1966) page 139 (as appearing in Journal of General Chemistry of the U.S.S.R., translated from Russian, 36 (1966) page 144), that 3,4,5,6-tetrafluorophthalic acid may be decarboxylated to yield 44% 2,3,4,5-tetrafluorobenzoic acid by heating for one hour at 145.degree. C. in dimethyl formamide. An unspecified amount of tetrafluorobenzene was found but it was not clear whether or not the amount of tetrafluorobenzene found accounts for the remainder of the starting material.
Under slightly more vigorous conditions, Japanese Patent Application 61/43130 A2[86/43130]as abstracted in CA106 (1):4629S and Derwent, accession number 86-097893/15, discloses that 3,4,5,6-tetrafluorophthalic acid may be completely decarboxylated to 1,2,3,4-tetrafluorobenzene in an aqueous medium from 210.degree. to 300.degree. C. In the presence of a catalyst, such as powdered metallic copper, zinc, cadmium, iron, cobalt or nickel or acids, hydroxides or carbonates of those metals the complete decarboxylation proceeds at temperatures as low as 100.degree. C. and preferably from 160.degree.-240.degree. C.
U.S. Pat. No. 4,782,180 discloses that 3,4,5,6-tetrafluoropthalic acid may be decarboxylated to form tetrafluorobenzoic acid. The reaction may be carried out in polar aprotic solvents and requires the presence of a base catalyst. Although organic amines are preferred, inorganic bases such as sodium bicarbonate, potassium carbonate, and sodium hydroxide may also be used. Potassium carbonate as a catalyst apparently leads to monodecarboxylation, whereas the carbonate of copper, zinc, cadmium, iron, cobalt, or nickel would lead to total decarboxylation, as reported in Japanese Patent application 61/43130 A2 (86/43130).
U.K. Patent 2,122,190 discloses that tetrafluoroterphthalic acid, in which the carboxyl groups are para to one another, readily decarboxylates in polar aprotic solvents to form 1,2,4,5-tetrafluorobenzene. The process may be conducted at temperatures as low as 100.degree. C. No catalyst is required, although a copper oxide catalyst may be used if desired.
Japanese Patent Application 86/290399 as abstracted in CA109 (19) 170038e discloses that 3,5,6-trifluoro-4-hydroxyphthalic acid may be decarboxylated by heating the compound for three hours, in water, under nitrogen atmosphere, at 140.degree. C. (in a sealed tube) to yield 2,4,5-trifluoro-3-hydroxybenzoic acid.
Aroskar et al (J. Chem. Soc. (1964) 2975) discloses a method for preparing 3,4,6-trifluorophthalic acid. They found that upon slowly heating a mixture of the acid and soda lime to 300.degree. C., they obtained a low yield of the fully decarboxylated 1,2,4-trifluorobenzene.
Japanese Patent JP 01/52737 discloses the preparation of 2,4,5-trifluorobenzoic acid by the decarboxylation of 3,4,6-trifluorophthalic acid in a liquid medium at a temperature of 80.degree.-250.degree. C. The liquid media disclosed include water, DMSO, tetramethyl sulfone, DMF, dimethylacetamide, N-methylpyrrolidone, acetonitrile, nitrobenzene, diethylene glycol, dimethyl ether, tetraethylene glycol, dimethyl ether, and tertiary amines such as tributyl amine, and dimethyl aniline. The patent further discloses that a catalyst such as the ammonium or alkaline earth metal salts of hydroxide, carbonate, bicarbonate, sulfate or fluoride may be used.
In U.S. Pat. No. 4,935,541, the present inventors have disclosed a process for the preparation of 2,4,5-trifluorobenzoic acid by decarboxylation of 3,4,6-trifluorophthalic anhydride at elevated temperatures in apolar, aprotic solvent, preferably in the presence of a copper catalyst.